NCI-sponsored trial for the evaluation of safety and preliminary efficacy of 3'-deoxy-3'-[18F]fluorothymidine (FLT) as a marker of proliferation in patients with recurrent gliomas: preliminary efficacy studies

Abstract

Purpose: 3'-Deoxy-3'-[18F]fluorothymidine ([18F]FLT) is being developed for imaging cellular proliferation. The goals were to explore the capacity of FLT-positron emission tomography (PET) to distinguish between recurrence and radionecrosis in gliomas and compare the results to those obtained with 2-fluoro-2-deoxy-D: -glucose (FDG).

Procedures: Fifteen patients with tumor recurrence and four with radionecrosis, determined by clinical course and magnetic resonance imaging results, were studied by dynamic [18F]FLT-PET with arterial blood sampling. A two-tissue compartment four-rate constant model was used to determine metabolic flux (K (FLT)), blood to tissue transport (K (1)), and phosphorylation (k (3)). FDG-PET scans were obtained 75-90 min postinjection.

Results: K (FLT) and k (3), but not K (1) or k (3)/k (2) + k (3), reached significance for separating the recurrence from radionecrosis groups. Standardized uptake value and visual analyses of FLT or FDG images did not reach significance.

Conclusions: K (FLT) (flux) appears to distinguish recurrence from radionecrosis better than other parameters, FLT and FDG semiquantitative approaches, or visual analysis of images of either tracer.

Fig. 1

The kinetic model of FLT metabolism is comprised of an exchangeable tissue compartment (Q_e) and a compartment of trapped FLT nucleotides (Q_m). Four rate constants (K₁–k₄) describe the kinetic transfer rates between the two compartments and blood. FLTMP FLT-monophosphate, FLTDP FLT-diphosphate, FLTTP FLT-triphosphate, FLT-gluc FLT-glucuronide synthesized in the liver, C_pFLT concentration of FLT in arterial plasma, C_met concentration of metabolites in arterial plasma.

Fig. 2

Recurrence: Patient 17 was a 41-year-old woman who died 6 months after the FLT-PET study from progression of her recurrent glioblastoma multiforme. a MRI T1+Gd shows a large right frontal contrast-enhancing lesion at the time of her FLT-PET and FDG-PET scans. b MRI T1+Gd taken 2.5 months after the FLT-PET shows definite progression of the contrast enhancing disease. c FDG-PET of the same plane and time as in a shows that the tumor has uptake focally less than cortex but greater than white matter. d FLT-PET shows a high level of uptake corresponding to the MRI T1+Gd abnormality in a. e Mixture analysis image of the K₁ transport parameter. f Mixture analysis image of the K_FLT flux parameter. Note that the color scale is ten times less for f than for e.

Fig. 3

Radionecrosis: Patient 1, a 46-year-old man with a right temporal grade 2 oligodendroglioma diagnosed by biopsy 9 years before FLT-PET and treated with radiotherapy 53 months before FLT-PET. a MRI T1+Gd shows extensive contrast enhancement in the right temporal, frontal, and parietal lobes. b MRI T1+Gd obtained 13 months after the FLT-PET shows decidedly less volume of enhancement. c FDG-PET of the same plane and time as a shows that the tracer uptake is focally greater than white matter but less than cortex. d FLT-PET shows a high level of uptake corresponding closely to the MRI T1+Gd abnormality in a. e Mixture analysis image of the K₁ transport parameter. f Mixture analysis image of the K_FLT flux parameter. Note that the color scale is ten times less for f than for e.

Fig. 4

Box plots showing the comparisons between the radionecrosis and recurrence groups for K_FLT, k₃, K₁, k₃/k₂+k₃, FLT SUV 15–60 min, FLT SUV_max 15–60 min, FLT SUV T/C 15–60 min, and FLT SUV_max T/WM 15–60 min. See Table 3 for p values.

Fig. 5

Correlations between K_FLT and SUV 15–60 (a) or SUV_max 15–60 (b) were poor (n=19). R² values were only 0.22 and 0.23, respectively.

Fig. 6

Box plots showing the comparisons between the radionecrosis and recurrence groups for FDG SUV, FDG SUV_max, FDG SUV T/C, and FDG SUV T/WM. See Table 5 for p values.